Pyridazines. Part 35: [1] Traceless Solid Phase Synthesis of 4,5- and 5,6-Diaryl-3(2H)-pyridazinones

Abstract

A new method for the traceless solid phase synthesis of 3(2H)-pyridazinones has been developed employing dihydropyran-functionalized resin. The procedure has permitted the preparation of several diarylpyridazinones through a Suzuki cross-coupling reaction and cleavage conditions that promoted a retro-ene fragmentation.

solid phase - pyridazinone - ene-adducts - palladium

References

1

For the previous paper in this series, see: Sotelo, E.; Raviña, E. Tetrahedron Lett., in press.

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4 Frank H. Heinisch G. Pharmacologically Active Pyridazines. Part 2. In Progress in Medicinal Chemistry   Vol. 29:  Ellis GP. Luscombe DK. Elsevier; Amsterdam: 1992.  p.141 

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9a Estévez I. Coelho A. Raviña E. Synthesis  1999,  9:  1666 

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11 de Leval X. Delarge J. Somers F. Tullio PD. Henrotin Y. Pirotte B. Dogné JM. Curr. Med. Chem.  2000,  7:  1041 

12

Selected physical and spectroscopic data of representative compounds 2. Compound 2a: Yield: 89%, mp 237-238 °C. IR (KBr): 3100, 1680 cm^-1. ¹H NMR (300 MHz, CDCl₃):
δ = 7.55-7.47 (m, 5 H, Ph), 7.40 (s, 1 H, CH), 5.58 (d, J = 8.1 Hz, 2 H, CH₂), 4.74 (t, J = 8.1 Hz, 1 H, OH). Compound 2b: Yield: 70%, mp 113-114 °C. IR (KBr): 3400, 2960, 1670 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): 8.19 (s, 1 H, CH), 6.97 (t, J = 7.6 Hz, 1 H, OH), 5.34 (d, J = 7.6 Hz, 2 H, CH₂).

13 Coelho A. Raviña E. Sotelo E. Synlett  2002,  12:  6062 

14 Ripoll J. Vallé Y. Synthesis  1993,  659 

15

General Procedure for the Preparation of Immobilized Pyridazinones 3: The amount of 300 mg of Ellman’s resin (Aldrich, 0.420 mmol) was loaded into a reactor on a PLS 6 × 4 organic synthesizer (Advanced ChemTech) and treated with 2 (1.26 mmol), PPTS (0.63 mmol) and dichloroethane (4 mL). The mixture was heated at 70 °C during 12 h, drained, washed sequentially with dichloroethane (3 × 5 mL), CH₂Cl₂ (3 × 5 mL), DMF (3 × 5 mL), CH₂Cl₂ (3 × 5 mL), MeOH (3 × 5 mL), Et₂O (3 × 5 mL) and dried in a vacuum dessicator.

16a Miyara N. Yanagi T. Suzuki A. Synth Commun.  1981,  11:  513 

16b Tsuji J. Palladium Reagents and Catalysts   Wiley; Chichester: 1995. 

17

General Procedure for Suzuki Arylation of Immobilized Halopyridazinones 3: The amount of 100 mg of pyridazinone-derivatized support 3 (0.120 mmol) was loaded into a reactor on a PLS 6 × 4 organic synthesizer (Advanced ChemTech) and treated with the appropriate boronic acid (0.300 mmol for 1a and 0.600 mmol for 1b,c), Pd(PPh₃)₄ (0.05 equiv), 2 M Na₂CO₃ (0.7 mL) and DME (3 mL). The mixture was heated at 70 °C during 12 h, drained, washed sequentially with DME (3 × 5 mL), DME/H₂O (3 × 5 mL), 0.2 N HCl (3 × 5 mL), EtOAc (3 × 5 mL), MeOH (3 × 5 mL), Et₂O (3 × 5 mL) and dried in a vacuum dessicator.

18

General Procedure for Cleveage of 4,5- and 5,6-Diarylpyridazinones Form Solid Support: The above resin (75 mg) was treated with 20% TFA in CH₂Cl₂ (2 mL) for 15 min. After filtration and washing with CH₂Cl₂ the combined filtrates were heated at 50 °C for 12 h, concentrated to give a residue wich was re-dissolved in a 1:1 mixture of CH₃CN-H₂O. The solvent was then removed under presure to give pyridazinones 6 and 7.

19

Selected physical and spectroscopic data of compounds 6 and 7: Compound 6a: Mp 135-136 °C. IR (KBr): 3100-2600, 1642 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 13.05 (br s, 1 H, NH), 7.74 (s, 1 H, CH), 7.04-6.92 (m, 10 H, Ph). Compound 6b: Mp 147-149 °C. IR (KBr): 3100-2600, 1639 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 13.16 (br s, 1 H, NH), 7.90 (s, 1 H, CH), 7.52-7.00 (m, 8 H, Ph), 2.24 (s, 6 H, 2 × CH₃). Compound 7a: Mp178-180 °C. IR (KBr): 3100-2600, 1668, 1589 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.58 (br s, 1 H, NH), 7.38-7.20 (m, 10 H, Ph), 7.01 (s, 1 H, CH). Compound 7b: Mp 198-200 °C. IR (KBr): 3100-2600, 1642 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 11.40 (br s, 1 H, NH), 7.41-7.29 (m, 5 H, Ph), 7.18 (d, J = 8.0, 2 H, phenyl), 7.07 (d, J = 8.0, 2 H, phenyl), 7.01 (s, 1 H, CH), 2.33 (s, 3 H, CH₃).

20

HPLC analyses were performed using a 5 µm 4.6 × 150 mm reverse phase column (70% acetonitrile/30% H₂O) over 40 min, flow rate 0.5 mL/min.